The goal of this project is to elucidate the mechanisms by which the AP-1 transcription factor JunB regulates normal hematopoiesis, and to understand how loss of JunB alters hematopoietic stem cells (HSC) properties and leads to the generation of leukemic stem cells (LSC). These studies will be carried out in mouse models of JunB deficiency that we have generated and characterized. Studies in Specific Aim 1 will investigate how deregulated cell cycle distribution and increased proliferation contribute to the aberrant properties of junB- deficient HSC. We will determine to what extent quiescent vs. cycling junB-deficient HSC are able to provide long-term engraftment, investigate their response to hematopoietic stresses and interrogate the molecular networks controlling their proliferation. These experiments should address the question of how HSC maintenance and proliferation are co-coordinately regulated to ensure homeostasis and how changes innts should increase our understanding of how HSC are maintained in their bone marrow niches and how LSC can escape these microenvironmental regulations. The general goal of Specific Aim 3 is to identify junB target genes in HSC. We will exploit both genome-wide bioinformatics approach to scan for genes with cis-regulatory motifs matching canonical JunB binding sites and chromatin immunoprecipitation (ChIP) approach with genomic array platforms (ChIP-chip). These experiments should uncover important regulatory networks controlling HSC homeostasis and transcriptional abnormalities underlying LSC generation. In Specific Aim 4, we will functionally evaluate the contribution of deregulated proliferation and microenvironmental interactions to the leukemic transformation of junB-deficient HSC. We will test the role of several important candidate genes by either correcting their defective regulation in junB-deficient HSC or by mimicking their alterations in normal HSC. These experiments should identify critical mediators that functionally contribute to LSC generation and function. PROJECT NARRATIVE: Together, these experiments pursue the general goal of identifying molecular targets to destroy the otherwise therapeutically resistant LSC population in human myeloid leukemias. 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